Dermatofibrosarcoma protuberans or DFSP is a sarcoma of low malignant potential.
Its importance lies in its locally aggressive behavior which may necessitate
a wide surgical excision with repeated local recurrences.

Multiple spindle cell lipomas and dermatofibrosarcoma protuberans within
a single patient: Evidence for a common neoplastic process of interstitial
dendritic cells?

Harvell JD.

Department of Pathology, Stanford University Medical Center.

J Am Acad Dermatol 2003 Jan;48(1):82-5 Abstract quote

This case report describes a 48-year-old man with multiple spindle
cell lipomas of the neck and a dermatofibrosarcoma protuberans (DFSP)
with fibrosarcomatous transformation of the chest. The presence of familial
and nonfamilial multiple spindle cell lipomas within a single patient
is a rare event, with only two reports in the current literature.

This case represents the first report of multiple spindle cell lipomas
occurring in association with a DFSP. It is of particular interest in
that both spindle cell lipoma and DFSP represent, at least in part,
neoplastic proliferations of CD34(+) spindled cells. The exact nature
and differentiation of these spindled cells remains controversial, but
prior studies have suggested that they could represent neoplastic interstitial
dendritic cells.

The association of DFSP and spindle cell lipoma within this single
patient suggests that these two tumors (and their histologic variants)
may well be linked, conceptually, as neoplastic proliferations of CD34(+)
interstitial dendritic cells.

NUCHAL TYPE FIBROMA

Dermatofibrosarcoma protuberans association with nuchal-type fibroma.

Hafeez Diwan A, Horenstein MG.

Department of Pathology, University of Texas - M. D. Anderson Cancer Center, Houston, TX, and Department of Pathology, University of South Alabama, Mobile, AL, USA.

J Cutan Pathol. 2004 Jan;31(1):62-6 Abstract quote.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a hypercellular, storiform, CD34-positive low-grade sarcoma with honeycomb entrapment of fat, which typically involves the trunk and extremities. Nuchal-type fibroma (NTF ) is a paucicellular, CD34-positive fibrous tumor with fat entrapment, which may occur in both nuchal and extranuchal locations and in association with Gardner syndrome.

METHODS: We report the association of DFSP with NTF in a 43-year-old male with no personal or family history of Gardner syndrome.

RESULTS: The patient had a past history of a DFSP removed from his back, which recurred 2 years later and was re-excised. Additionally, the patient had a typical NTF, in the posterior neck, removed at the same time. Histopathologic examination of the recurrent back lesion demonstrated a composite lesion with typical appearances of DFSP, centrally, blending into an NTF-like appearance, peripherally. Both components expressed CD34 and CD99, and lacked elastin. A review of the microscopic slides of the patient's previously excised DFSP revealed an identical lesion with surrounding NTF-like areas.

CONCLUSION: While an association between NTF and fibromatosis has recently been reported, this is to our knowledge the first report of an association between NTF and DFSP. The morphologic findings suggest that there may be a continuum between these two CD34-positive lesions that have a tendency to infiltrate adipose tissue and recur.

Dermatofibrosarcoma protuberans (DFSP) is a cutaneous, locally aggressive spindle cell tumor of intermediate malignancy. Tumor cells are reactive for CD34 and characterized by a t(17;22) translocation or a supernumerary ring chromosome that results in the fusion of exon 2 of PDGFB to various exons of the COL1A1 gene.

Three novel COL1A1 breakpoints were identified, intronic between exons 13:14 (1), 30:31 (1) and in exon 49 (2). There was no correlation found between breakpoints and age, sex, or histologic variants. Using this sensitive multiplex RT-PCR assay in combination with fluorescence in situ hybridization, we found COL1A1-PDGFB rearrangements appear more prevalent in DFSP than previously reported. Its detection may be particularly helpful in the differential diagnosis of atypical, fibrosarcomatous, and metastatic DFSP.

Dermatofibrosarcoma protuberans is a superficial low-grade sarcoma that rarely evolves into a high-grade fibrosarcoma. Dermatofibrosarcoma protuberans is genetically characterized by the unbalanced chromosomal t(17;22)(q21;q13), usually in the form of a supernumerary ring chromosome. The product of this chromosomal translocation is the chimeric gene COL1A1-PDGFB (collagen type I alpha I-platelet-derived growth factor beta), which is amplified at low levels in the ring chromosome.

The aims of this study were to evaluate (1) whether genomic gains of this fusion gene occur during the clonal evolution of dermatofibrosarcoma protuberans into fibrosarcomatous dermatofibrosarcoma protuberans and (2) whether there is a difference between the number of genomic copies of COL1A1-PDGFB between classic dermatofibrosarcoma protuberans and dermatofibrosarcoma protuberans areas associated with fibrosarcomatous dermatofibrosarcoma protuberans. Eleven cases of fibrosarcomatous dermatofibrosarcoma protuberans with both dermatofibrosarcoma protuberans and fibrosarcomatous areas and 10 cases of classic dermatofibrosarcoma protuberans were studied. Genomic copies of COL1A1-PDGFB were evaluated by fluorescence in situ hybridization using a custom designed probe for the PDGFB locus on 4 mum thick paraffin-embedded tissue sections. Genomic gains of the COL1A1-PDGFB gene were observed in six (of 10) fibrosarcomatous dermatofibrosarcoma protuberans in the fibrosarcomatous areas when compared to the dermatofibrosarcoma protuberans areas of the same tumor (2-7 gene copies (median PDGFB copy gain, 2.8) versus 1-3 gene copies (median PDGFB copy gain, 1.7), respectively, P=0.004). Four fibrosarcomatous dermatofibrosarcoma protuberans did not show genomic gains of COL1A1-PDGFB fusion gene between the two areas. Essentially no difference in the copy number of COL1A1-PDGFB fusion gene was observed between dermatofibrosarcoma protuberans areas of classic dermatofibrosarcoma protuberans and dermatofibrosarcoma protuberans areas of fibrosarcomatous dermatofibrosarcoma protuberans (median PDGFB copy gain of 1.8 versus 1.7, respectively, P=0.36). Genomic gains of COL1A1-PDGFB fusion gene is possibly an oncogenic mechanism that is identified in the clonal evolution of a subset of dermatofibrosarcoma protuberans that evolves into fibrosarcomatous dermatofibrosarcoma protuberans.

Since this finding was not observed in all cases of fibrosarcomatous dermatofibrosarcoma protuberans, other oncogenic mechanisms may be operating in this form of tumor progression. Copy number of COL1A1-PDGFB fusion gene in the classic dermatofibrosarcoma protuberans areas does not seem to be a major predisposing mechanism for fibrosarcomatous transformation.

COL1A1-PDGFB Gene Fusion Demonstrates a Common Histogenetic
Origin for Dermatofibrosarcoma Protuberans and Its Granular Cell Variant.

Granular cell variant of dermatofibrosarcoma protuberans is very rare
with only one report of two cases.

We report a new case in which we demonstrated the presence of the dermatofibrosarcoma
protuberans-specific COL1A1-PDGFB fusion from paraffin-embedded tissue.
This case analysis demonstrated the utility of molecular genetics as
a powerful tool for the diagnosis of atypical forms of dermatofibrosarcoma
protuberans.

The clinicopathologic and immunohistochemical features of 28 dermatofibrosarcoma
protuberans (DFSP), giant cell fibroblastomas (GCFs), and hybrid lesions
occurring in children are presented, including molecular data for seven
of them.

One karyotyped adult-type DFSP showed an unbalanced t(17;22) (q22;q13)
translocation. Multiplex RT-PCR analysis and sequencing of PCR products
in seven cases showed gene fusion transcripts in two pure DFSP, two
pure GCFs, and one hybrid lesion. Results were uncertain in one pure
GCF; one adult-type DFSP was negative. Treatment procedures were known
for 27 patients, consisting of 16 wide excisions and 11 marginal excisions.

Follow-up information on 15 widely excised tumors (median 24 months;
range 5-144 months) showed no recurrence. Five of six marginally excised
lesions with available follow up recurred 2 months to 6 years (median
2 years) after initial surgery; all but one were cured by wide reexcision.
None of the tumors metastasized.

In conclusion, this study emphasizes 1) the occurrence of adult-type
DFSP in children, 2) the close relationship between DFSP and GCF clinically,
histologically, and molecularly, 3) the excellent prognostic of these
lesions if widely excised, and 4) the diagnostic usefulness of RT-PCR
analyses in detecting the gene fusion transcripts resulting from the
t(17;22) (q22;q13) in paraffin-embedded tissues.

Dermatofibrosarcoma protuberans (DFSP) is a dermal and subcutaneous tumor categorized as a tumor of intermediate malignancy, and its progression in some cases to fibrosarcoma is well known. However, molecular analysis of tumor progression has been limited. The present study investigated microsatellite instability (MSI) of 7 microsatellite markers through high-resolution microsatellite analysis in addition to a mutational analysis of the p53 gene in 44 tumors in 36 patients.

The patients were divided into 2 groups: 9 patients with a fibrosarcomatous component in the primary or recurrent/metastasized tumor, designated as the DFSP+FS group, and the remaining 27 patients, designated as the DFSP group. Cases in which the percentage of markers with an additional peak among the markers successfully analyzed was more than 30% was considered MSI high (MSI-H); cases in which microsatellites were stable at all of the successfully examined markers were considered microsatellite stable (MSS); and the remaining cases were considered MSI low (MSI-L). MSI-H cases were observed more frequently in the DFSP+FS group (4 of 9 cases) than in the DFSP group (1 of 27 cases) (P = 0.028, Fischer's exact test). The MSI status of recurrent or metastatic tumors in both the DFSP+FS and the DFSP groups was the same as that in the corresponding primary neoplasms.

Furthermore, there was no difference in MSI status between an ordinary DFSP area and a fibrosarcomatous area in 7 tumors that exhibited both areas. p53 mutational analysis revealed 10 point mutations, composed of 4 missense mutations and 6 silent mutations, in 6 of 36 cases (16.7%). A missense mutation was more frequently observed in the DFSP+FS group (3 of 4) than in the DFSP group (1 of 4). Among 3 cases of a missense mutation in the DFSP+FS group, 2 had a mutation only in a fibrosarcomatous area and 1 had a mutation only in a metastatic tumor progressing to fibrosarcoma.

These results suggest that MSI and p53 mutations are involved in tumor progression of DFSP to fibrosarcoma as early and late events, respectively.

RING CHROMOSOME

Dermatofibrosarcoma protuberans: report of a case with a variant ring chromosome and metastases following pregnancy.

Background: The most frequent molecular abnormality observed in dermatofibrosarcoma protuberans (DFSP) is the formation of a supernumerary ring chromosome or translocation resulting in fusion of the gene encoding the alpha-chain of type 1 collagen, COL1A1 from 17q22, to the platelet-derived growth factor beta-chain, PDGFB gene from 22q13. Rare cases documenting variant ring or marker chromosomes involving regions other than 17q22 and 22q13 have been reported. Further analysis in three of these cases demonstrated the presence of the COL1A1 and PDGFB genes.

Methods: We report a further case of DFSP with a rare variant ring chromosome. The tumor appeared to undergo accelerated growth during pregnancy, then metastasized following pregnancy. We describe the clinical, histological, immunohistochemical, and cytogenetic features.

Results: The metastatic tumor showed a variant r(17;?) chromosome. A locus-specific probe was required to demonstrate presence of the PDGFB gene within the ring, indicating cryptic molecular rearrangement between chromosomes 17 and 22, and recombination with an unknown chromosome.

Conclusions: Cryptic rearrangement of chromosomes 17 and 22 should be suspected in variant ring chromosomes and translocations. Pregnancy may contribute to accelerated growth of DFSP, and delay in surgical resection should be avoided.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon low-grade
fibrohistiocytic tumor that usually occurs on the trunk or proximal
extremities and typically appears during the second to fifth decade
of life. It most commonly begins as a red-blue plaque that grows slowly
and ultimately becomes nodular. The tumor is associated with a high
recurrence rate but low metastatic potential. It rarely presents in
childhood and is even more rarely present at birth. The clinical diagnosis
of DFSP in infancy or childhood may be difficult because, in its early
stages, the tumor often resembles a vascular birthmark.

OBSERVATIONS: We studied 6 patients with congenital DFSP who were initially
thought to have other diagnoses, highlighting the potential clinical
variability in presentation. Half of the cases in this series occurred
in areas of the body outside of the typically reported distribution
pattern of acquired DFSP and in locations that, therefore, may not arouse
suspicion of congenital DFSP.

CONCLUSIONS: Given the aggressive local potential and high recurrence
rate of DFSP, early diagnosis is preferable to facilitate appropriate
excision. We recommend that any infant or child presenting with a cutaneous
plaque or nodule, even congenital, that does not have characteristic
or diagnostic clinical features undergo tissue biopsy for histologic
evaluation.

VULVA

Dermatofibrosarcoma protuberans of the vulva and groin: detection of
COL1A1-PDGFB fusion transcripts by RT-PCR.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is an uncommon infiltrative
tumor of the dermis with characteristic cytogenetic features, specifically
the translocation t(17;22)(q22;q13) which often manifests as a supernumerary
ring chromosome r(17;22). The translocation results in the fusion of
two genes, collagen type I alpha 1(COL1A1) and platelet-derived growth
factor B-chain (PDGFB). The trunk and extremities are the anatomic sites
of predilection for DFSP, whereas the vulva and groin are quite uncommon
sites of involvement.

RESULTS: Six of seven cases (three vulvar, three groin) contained a
COL1A1-PDGFB fusion transcript. Sequence analysis of the PCR products
revealed that the break-point of the COL1A1 gene was located after exon
40 in two patients, after exon 42 in one patient, after exon 44 in one
patient, and after exon 47 in two patients; the break-point in the PDGFB
gene was before exon 2 in all cases. No fusion transcript could be amplified
in one case.

CONCLUSIONS: As in DFSP at other sites, COL1A1- PDGFB chimeric fusion
transcripts are present in vulvar and groin DFSP. The transcripts can
be detected in formalin-fixed, paraffin-embedded tumor tissues, and
have the same general pattern of exon boundaries as in DFSP at other
sites.

HISTOLOGICAL TYPES

CHARACTERIZATION

GENERAL

A morphologic study of dermatofibrosarcoma protuberans:
expansion of a histologic profile.

Dermatofibrosarcoma protuberans (DFSP) is a fibrohistiocytic tumor
of intermediate malignancy characterized by a distinctive storiform
growth pattern and frequent local recurrences.

In this study, we retrospectively reviewed 48 cases of DFSP diagnosed
at the Cleveland Clinic Foundation between 1970 and 1999 to determine
the prevalence of morphologic variations including the presence of giant
cell fibroblastoma (GCF)-like areas, multinucleated giant cells, hypercellular
zones and fibrosarcomatous change.

Our findings suggest that DFSP has a wider range of morphologic features,
including GCF-like areas, multinucleated giant cells, hypercellular
zones and fibrosarcomatous change, than has been previously recognized
in the literature.

VARIANTS

ATROPHIC

Atrophic dermatofibrosarcoma protuberans: a case report and review of
the literature.

Fujimoto M, Kikuchi K, Okochi H, Furue M.

Department of Dermatology, Tokyo University Branch Hospital, Japan.

Dermatology 1998;196(4):422-4 Abstract quote

Dermatofibrosarcoma protuberans is not a difficult tumor to recognize
because of its characteristic clinical appearance, although some unusual
variants have been reported.

We describe the atrophic variant of dermatofibrosarcoma protuberans
in a 21-year-old female. The lesion was a smooth-surfaced, oval depression
on the left subclavicular area, with a violaceous plaque at the center.
The suspected clinical diagnosis did not include fibrous tumors, although
histological examination showed the typical picture of dermatofibrosarcoma
protuberans. Positive CD34 staining was also helpful in the diagnosis.

We review 14 cases of the atrophic variant of dermatofibrosarcoma protuberans
in the literature. Dermatologists should be aware of this uncommon but
characteristic appearance of atrophic dermatofibrosarcoma protuberans.

BACKGROUND: Neuroectodermal differentiation or melanocytic colonization
are the opposing theories of histogenesis for the Bednar tumor or pigmented
dermatofibrosarcoma protuberans (DFSP).

OBSERVATION: A 31-year-old African-American woman presented with a
2-cm blue-black shoulder nodule of 1-year duration. Punch biopsy revealed
a CD34+, Factor XIIIa-DFSP, harboring numerous, pigmented spindle S100+,
Mart-1+ and HMB-45+ cells. Subsequent wide excision demonstrated pigmented
dendritic and spindled cells widely scattered throughout the dermis
of the 3-cm excisional margins and punch biopsy specimens of normal
skin from both shoulders. This latter process was interpreted as dermal
melanocytosis (nevus of Ito). The dermal pigmented spindle cells were
Mart-1+ and CD34-, and were associated with non-pigmented CD34+, cytologically
banal spindle cells, which were more numerous in the excisional margins
than the contralateral shoulder.

CONCLUSION: Reported herein is a singular case of Bednar tumor associated
with dermal melanocytosis. Although the coexistence of these processes
implicates colonization of the DFSP by constituent dermal melanocytes,
the mixed immunophenotype (CD34+ or Mart-1+ cells) of dispersed dermal
spindle cells hints at the possibility of a common cell of origin: the
putative neuromesenchymal cell. In effect, the Bednar tumor could represent
one part of a spectrum of neural crest-derived dermal tumors that includes
dermal melanocytosis, cellular blue nevus and conventional DFSP.

The myxoid variant of dermatofibrosarcoma protuberans (DFSPs) is uncommon. It often presents a diagnostic challenge and is important to recognize to prevent both undertreatment and overtreatment.

To better characterize this unusual variant of DFSP, 23 myxoid DFSPs (DFSP with greater than 50% myxoid stroma) were retrieved from the authors' consult files. 13 patients were male and 10 were female (median age 40 years; range 9 months to 72 years of age). Tumor size ranged from 1.5 to 11 cm (median 2.8 cm).

The most frequent sites were the extremities (9) and head and neck (7), followed by the trunk (4) and anogenital region (3). Grossly, the tumors were white/tan/gray to yellow, firm to gelatinous soft tissue masses.

Histologically, tumor stroma ranged from 50 to 100% myxoid (median 80%). The majority of cases displayed an infiltrative sheet-like proliferation of bland spindle cells with palely eosinophilic cytoplasm and stellate nuclei without pleomorphism. The stroma was myxoid with prominent thin-walled vessels. All cases displayed honeycomb infiltration of fat and 16 cases showed cellular areas of more typical DFSP. Four tumors contained pigmented dendritic cells (Bednar variant), 1 showed areas of giant cell fibroblastoma and 1 showed progression to fibrosarcomatous DFSP. Mitoses ranged from 0 to 5 per 10 high power fields. 95% of cases (21 out of 22) were positive for CD34 and all cases were negative for S100 and muscle markers. Clinical follow-up in 8 cases, ranging from 3-21 years, (median follow-up 6 years), revealed local recurrence in 2 cases and no evidence of metastasis. All patients were free of disease following wide excision or excision followed by radiotherapy.

In summary, these low-grade lesions are clinically similar to typical DFSP, but their unusual morphology is easily confused with a variety of other tumor types.

NEUROFIBROMATOUS CHANGE

Neurofibromatous changes in dermatofibrosarcoma protuberans: a potential pitfall in the diagnosis of a serious cutaneous soft tissue neoplasm.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) is a low-grade malignant neoplasm that has the potential for aggressive local growth and destruction if not treated appropriately. Although the storiform arrangement of spindle cells in DFSP is relatively characteristic, histologic patterns simulating other benign as well as malignant neoplasms such as dermatofibroma, neurofibroma, malignant fibrous histiocytoma, and atypical fibroxanthoma have been described.

METHODS: We collected and analyzed six cases of probable DFSP in which a specific diagnosis could not be rendered due to the predominant neurofibromatous changes in the histologic sections. In an attempt to reach a definitive diagnosis, the clinical history and physical characteristics of the lesions were taken into account, and all cases were further evaluated using immunostaining for CD34 and S-100 protein.

RESULTS: The average age of the patient was 56 years (range 21-80), and the male to female ratio was 1 : 1. The location of lesions included the scalp, neck, back, and abdomen. All cases displayed two distinct histological patterns: (i) a proliferation of spindle cells with wavy nuclei in a loose mucinous stroma suggesting neural differentiation and (ii) a proliferation of spindle cells which interweaved and filled the reticular dermis extending into the subcutis. The wide variety of clinical impressions and descriptions indicated that the diagnoses were not always straightforward, and clinical information did not always assist in the clinicopathologic correlation. All lesions stained positively for CD34; however, three of six cases also stained positively for S-100. The three cases which were CD34 positive and S-100 negative were likely DFSP, and this was the final diagnosis given. The three cases that were CD34 and S-100 positive did not allow for a straightforward diagnosis.

CONCLUSIONS: DFSP may demonstrate areas with features more characteristic of a benign neural lesion, such as a neurofibroma, which can lead to underdiagnosis and subsequent failure to treat. Clinicians and pathologists should recognize this potential diagnostic pitfall and understand that equivocal clinical information, combined with non-specific immunohistochemical staining patterns, can further complicate the dilemma. In these situations, where DFSP is the likely diagnosis but definitive evidence cannot be obtained, full excision of the lesion should be recommended to avoid mistreatment of a potentially malignant lesion.

Using gene microarray expression profiling, we previously found that apolipoprotein D (Apo D) was highly expressed in dermatofibrosarcoma protuberans (DFSP).

In this study, we confirm that Apo D is highly and relatively specifically expressed in DFSP using immunohistochemistry. A tissue microarray containing 421 soft tissue tumors was constructed and stained with antibodies against Apo D and CD34. Cytoplasmic immunostaining for Apo D was found in 9 of 10 typical DFSPs. In addition, 3 of 3 Bednar tumors and 2 of 3 giant cell fibroblastomas stained in conventional sections. In contrast, Apo D was immunoreactive in only a very small subset of a diverse collection of other soft tissue tumors, including Malignant Fibrous Histiocytoma (MFH), glomus tumor, neurofibroma, and malignant peripheral nerve sheath tumors. Immunostains for Apo D were negative in conventional sections of 16 fibrous histiocytomas, and an additional 12 variants of fibrous histiocytoma. Digital images of all immunohistochemical and hematoxylin and eosin tissue microarray stains are available at the accompanying website (http://microarray-pubs.stanford.edu/tma_portal/apod/).

We conclude that Apo D is strongly expressed in DFSPs and neural lesions and may be useful in differentiating DFSP from fibrous histiocytoma.

CD34

Br J Dermatol 1992;127:79-84
Am J Dermatopathol 1997;19:562-567

Positive

If a tumor undergoes sarcomatous transformation, the sarcomatous area
is also positive

CD44

CD44 and hyaluronate in the differential diagnosis of dermatofibroma
and dermatofibrosarcoma protuberans.

Calikoglu E, Augsburger E, Chavaz P, Saurat JH, Kaya G.

Department of Dermatology, Fatih University Medical School,
Ankara, Turkey, and Department of Dermatology, DHURDV, University Hospital
of Geneva, Geneva, Switzerland.

J Cutan Pathol 2003 Mar;30(3):185-9 Abstract quote

The histological distinction between dermatofibroma (DF) and dermatofibrosarcoma
protuberans (DFSP) may be extremely difficult. CD34 and Factor XIIIa
have been used to differentiate DF from DFSP. However, there is an overlap
and relative lack of specificity of their expressions. CD44 is a widely
distributed integral membrane glycoprotein, which is expressed as a
multitude of isoforms generated by alternative splicing of at least
10 different variant exons and post-translational modifications. CD44
is currently thought to be the principal cell surface receptor for hyaluronate
(HA), the major component of the extracellular matrix.

In this study we aimed to assess the expression of standard CD44 (CD44s)
and its isoforms (CD44v3, CD44v4, CD44v5, CD44v6, CD44v7, CD44v7v8,
and CD44v10), and HA in DF and DFSP. Immunohistochemical staining was
performed on the biopsy specimens of 15 cases of DF and four cases of
DFSP, using antibodies that recognize the CD44s, different CD44 isoforms
and the hyaluronate binding protein (HABP). Tumor cells displayed a
strong CD44s immunoreactivity in all cases of DF whereas a faint HA
positivity was observed in the tumor stroma. The DF cells were negative
for CD44v3, CD44v4, CD44v6, CD44v7 and CD44v7v8 but showed a strong
reactivity for CD44v5 and CD44v10.

In contrast, CD44s' expression was significantly reduced or absent
in all DFSP lesions and the tumor stroma displayed strong staining for
HA. Our results indicate that CD44 and HA can be used as additional
diagnostic markers to distinguish DF from DFSP.

CD117

A study of CD117 expression in dermatofibrosarcoma protuberans and cellular dermatofibroma.

Background: Dermatofibrosarcoma protuberans (DFSP) is a relatively uncommon spindle cell tumor of the skin. It is locally aggressive and can be a therapeutic challenge. There are case reports of partial response of DFSP to the tyrosine kinase inhibitor STI571 (Imatinib), despite the reported negativity of the tumor cells for CD117. At least one publication reported focal CD117 positivity of DFSP cells, and we would like to clarify the issue. Cellular dermatofibroma (CDF) can mimic DFSP, but typical cases are easily differentiated from DFSP by their staining pattern for CD34 and factor 13a. We also report our experience with CD117 staining of typical CDFs.

Methods: Thirty-seven cases of clear-cut DFSP and 13 cases of clear-cut CDF were retrieved from the archives of Sunnybrook Health Sciences Center between 2000 and 2005.

Conclusions: Our study on a relatively large number of cases confirms the negativity of DFSP and CDF for CD117. Therefore, if adjuvant therapy is attempted with drugs such as STI571 (Imatinib), the eligibility of patients should not be based on immunohistochemical assessment of CD117 expression.

Background: Distinction between cellular fibrous histiocytomas (FHs) with a deep component and dermatofibrosarcoma protuberans (DFSPs) can pose diagnostic problems. While CD68, CD34, and Factor XIIIa are helpful in distinguishing between these entities, none are diagnostically absolute. Recent work with CD163, a hemoglobin scavenger receptor, has demonstrated that this marker has high specificity for monocytes, macrophages, and histiocytes. Our goal is to evaluate the utility of CD163 in the diagnosis of dermatofibromas (DFs), cellular FHs, and DFSPs.

BACKGROUND: Dermatofibroma (DF) and dermatofibrosarcoma protuberans (DFSP) occasionally resemble each other histologically but differ in histogenesis and biological behavior. This study sought to determine if these lesions can be differentiated by the quantity or quality of expression of cyclooxygenase-2 (COX-2), an enzyme associated with both reactive and neoplastic processes.

PATIENTS AND METHODS: Formalin-fixed and paraffin-embedded samples from 20 DFs and 20 DFSPs were stained immunohistochemically with antibodies directed against COX-2. Staining was evaluated semiquantitatively for percentage and intensity using a three-tiered system. DFs were graded and analyzed by cellularity. Findings within the tumors were compared with fibrocyte staining in adjacent tissue. The results were analyzed.

CONCLUSIONS: COX-2 immunostaining does not distinguish DFs from DFSPs. However, the enzyme is expressed more widely and more intensely in more cellular, possibly younger, DFs. The prominent expression of COX-2 in DFSP may have clinical implications for treatment with COX-2 inhibitors in tumors that are not amenable to surgery.

FACTOR XIIIa

Rare positive cells but the majority of the spindle cells
are negative

Department of Pathology, Yale University School of Medicine, New Haven, CT 06504-8900, USA.

Am J Dermatopathol. 2004 Aug;26(4):267-72. Abstract quote

The histologic distinction of dermatofibrosarcoma protuberans (DFSP) and dermatofibroma (DF) may be difficult, especially in the case of DF extending into the subcutaneous fat (deep DF). CD34 and Factor XIIIa staining is commonly used in separating DF from DFSP, but is not always helpful. HMGA1 and HMGA2 genes, members of the high mobility group protein family genes, encode proteins that act as architectural transcription factors and are frequently dysregulated in a variety of benign or locally aggressive mesenchymal tumors.

In this study, we evaluated the immunoreactivity of HMGA1 and HMGA2 in a series of DF and DFSP to determine the possible utility for these markers in the differential diagnosis of these two entities. Immunohistochemical stains were performed on paraffin-embedded tissues from 22 cases of DF, including 14 cases of deep DF and 14 cases of DFSP, using antibodies against HMGA1 and HMGA2. CD34 and Factor XIIIa immunoreactivity was also evaluated in these lesions and compared with the results of HMGA immunostaining. Immunopositivity for both HMGA1 and HMGA2 was seen in 21of 22 (96%) DFs, but in only 3 (21%) and 1 (7%) of 14 DFSPs, respectively.

While 100% of DFSP stained for CD34, 36% of DF also labeled for CD34. The immunoreactivity of HMGA1 and HMGA2 in DF was generally strong and diffuse, in contrast to weak and focal staining seen in DFSP. The proportion of cases with positive immunoreactivity for both markers was significantly higher in DF and in deep DF than in DFSP (P < 0.001).

We conclude that HMGA1 and HMGA2 expression can be used to distinguish DF from DFSP with a degree of accuracy that is fully equivalent to that of Factor XIIIa and CD34.

Low-affinity nerve growth factor receptor (p75) is a member of the
tumor necrosis factor receptor family. It may modulate the binding of
nerve growth factor (NGF) to the functional high-affinity receptor tyrosine
kinase (trk) A. NGF is thought to be responsible for growth, apoptosis,
and function of the nervous system.

The presence of this receptor (p75) was determined in a large group
of neural and nonneural tumors and fetal and adult tissues. One thousand
one hundred fifty tumors were analyzed with monoclonal antibody for
p75, along with selected normal fetal and adult tissues. Immunoreactivity
for p75 was present in adult pericytes, perivascular fibroblasts, basal
cells of several types of epithelia, perineurial cells, and dendritic
reticulum cells. Additionally, a wide zone of subepithelial mesenchyme
and skeletal muscle were positive in the first-trimester fetus, but
were diminished or negative in the adult.

The presence of p75 in nonneural tumors such as DFSP and rhabdomyosarcoma
mimic its presence in early fetal mesenchyme and skeletal muscle, suggesting
oncofetal expression in these tumors. p75 may be useful to distinguish
DFSP from benign fibrous histiocytoma.

CONTEXT: Common fibrous histiocytoma (cFH) or dermatofibroma and dermatofibrosarcoma protuberans (DFSP) are 2 spindle cell mesenchymal tumors that are distinguished in part by their microscopic growth patterns and clinically by the greater propensity for DFSP to recur. Matrix metalloproteinases (MMPs) potentially play a role in modulating the growth patterns of cFH and DFSP by remodeling the extracellular matrix.

OBJECTIVE: To evaluate the immunohistochemical (IHC) expression of MMP-1, MMP-2, MMP-9, and MMP-14 in DFSP and cFH, because (1) MMP-1, MMP-2, MMP-9, and MMP-14 are synthesized by dermal fibroblasts, the major constituent of DFSP and cFH; and (2) platelet-derived growth factor B, which is overexpressed in most examples of DFSP because of t(17;22), activates ets-1, a transcription factor that regulates molecules associated with tumor invasion and metastasis, including MMP-1, MMP-3, and MMP-9.

CONCLUSION: Our IHC results indicate that MMP-1 and MMP-9 are not up-regulated in DFSP. Convincing expression of MMP-14 in cFH suggests that this MMP may affect the growth pattern of the lesion, perhaps by activating MMP-2 expression in tumor cells. In DFSP, MMP-2 may play a role in tumor angiogenesis.

Background: Stromelysin 3 (ST3) is a member of the metalloproteinase
family, which is expressed in tissue remodeling processes such as scarring,
embryogenesis, or tumoral invasion. Although the prognosis of breast
cancers and extracutaneous squamous cell carcinomas is correlated with
the level of expression of ST3, this staining has not yet found a routine
application in dermatopathology.

Objective: Our purpose was to study by immunohistochemistry the expression
of ST3 in dermatofibromas and dermatofibrosarcoma protuberans (DFP).

Methods: We selected 40 cases of dermatofibromas, 40 histologically
typical DFPs, and 10 giant dermatofibromas. Immunohistochemistry was
carried out by means of the LSAB method, with monoclonal anti-ST3 antibody
(provided by MC Rio, IGBMC Strasbourg). A semiquantitative scale (0-3)
was used to evaluate the level of ST3 expression.

Results: Positively stained cells were observed in all cases of dermatofibromas
(100%), including the 10 giant cases, but never in DFP (0%). The staining
was intense (class 2 or 3) in 39 of the 50 dermatofibromas. The CD34
staining used as a control proved to be less efficient; 6 DFP were CD34
negative, whereas some of the dermatofibromas showed a marginal CD34
positivity.

Conclusion: Our results are consistent with those obtained by in situ
hybridization in previous studies of smaller series of fibrous tumors.
The study of ST3 expression in fibrous tumors of the skin shows that
this immunostaining could be a useful tool in the purpose of differentiating
DFP from giant or invasive dermatofibromas. Although ST3 is a negative
marker for DFP and therefore does not demonstrate the margins of the
neoplasm, it is more reliable than CD34 staining in differentiating
this tumor from a dermatofibroma.

From the Departments of Pathology (M.G.H., V.G.P., J.D.N., J.L.B.,
C.R.S.) and Medicine (Dermatology; V.G.P., C.R.S.), Duke University
Medical Center, Durham, North Carolina; and the Department of Pathology
(M.G.H.), University of South Alabama Medical Center, Mobile, Alabama

The authors report 10 cutaneous fibrohistiocytic lesions combining
clinical, histologic, and immunohistochemical features of both DF and
DFSP. The lesions had an average size of 1.2 cm (range, 0.4–2.7 cm),
and occurred on the trunk (n = 6), extremities (n = 3), and face (n
= 1) of four men and six women (average age, 30.6 yrs; age range, 15–50
yrs). Eight lesions exhibited acanthosis and densely cellular fascicles
with focal storiform areas. All had keloidal collagen, infiltrated the
subcutis in a honeycomb pattern, and had low mitotic counts (0 to 4
mitoses per square millimeter). All were diffusely immunoreactive for
factor XIIIa (30%–60% of the neoplastic cells) as well as CD34 (20%–70%).

This series raises the possibility of a biologic spectrum between DF
and DFSP; however, double-immunolabeling studies showed no notable coexpression
of factor XIIIa and CD34 by individual cells, suggesting coexistence
of two different cellular populations. After an average follow up of
22.3 months (range, 10–46 mos) in six cases, a single recurrence was
documented. The ambiguous histologic features and the potential for
local recurrence suggest that performing a complete excision may be
prudent in these diagnostically indeterminate lesions.

Methods: We collected 14 acral fibrocytic lesions showing a spindle cell morphology from our files, and evaluated CD34, Factor XIIIa, epithelial membrane antigen (EMA), and S100 protein staining of these lesions. We compared the histologic and immunohistochemical features of these cellular fibromas with five digital AFs, five ADFs, and five digital dermatofibromas.

Results: The 14 cellular digital fibromas showed intersecting fascicles of thin delicate bland spindle cells in the superficial reticular dermis with a fibrotic-to-slight myxoid stroma. The spindle cells in all cases stained strongly for CD34, and only scattered stromal cells stained for Factor XIIIa. Five tested cases were negative for EMA and S100 protein. The digital AFs, fibrokeratomas, and dermatofibromas stained predominately for Factor XIIIa, with no or minimal staining for CD34.

Conclusions: These findings suggest that a subset of digital fibromas is characterized by a dense cellular proliferation of CD34-positive spindle cells. Awareness of this variant of digital fibroma and its staining pattern is critical in preventing misdiagnosis as dermatofibrosarcoma protuberans, particularly in superficial biopsies.

Dermatofibrosarcoma protuberans (DFSP) is a superficial tumor characterized by high rates of local recurrence and a small risk of metastasis. Fibrosarcomatous (FS) areas rarely arise in DFSP, and considerable controversy exists as to whether these tumors have a higher risk of metastasis than the typical DFSP.

The aim of this study was to reappraise the prognostic significance of FS changes in DFSP by analyzing 41 patients from the consultation files of our institution. The study included 23 females and 18 males, with a median age of 48 years (range, 16-100 years). Eighteen lesions were located on the trunk, 16 on the extremities, and 7 on the head/neck region. All tumors were treated with local excision, and the surgical margins were considered positive for tumor in 22 of 39 cases (56%). Fibrosarcomas arose de novo in 38 cases and as a recurrence in 3 cases. All tumors involved the dermis and subcutis, and the FS component comprised 5% to 95% of the tumor area (median, 60%). Mitotic rates of the FS component (median, 20 mitoses/10 high-power fields [HPFs]; range, 5-48/10 HPFs) were considerably higher than those of the neighboring DFSP component (0-2 mitoses/10 HPFs).

Immunohistochemical analyses showed that CD34 expression was stronger and more extensive in the DFSP component (97% positive; median intensity, 3+) than in the FS component (81% positive; median intensity, 2+). The MIB-1 labeling index was higher in the FS areas (median, 20%; range, 5%-45%) than in the DFSP areas (<3%). Expression of p53 was present in 92% of the FS areas and in only 3% of adjacent DFSP areas. Follow-up data revealed that 8 patients had local recurrences, 4 patients (10%) had metastases, and 2 patients died of disease. None of the variables evaluated, including margin status, FS proportion, and mitotic count, correlated with disease progression.

We demonstrate that FS change in DFSP is a form of tumor progression that carries an increased risk of metastasis over classic DFSP and is associated with gains of p53 mutations and increased proliferative activity.

Sarcomas Arising in Dermatofibrosarcoma Protuberans A Reappraisal
of Biologic Behavior in Eighteen Cases Treated by Wide Local Excision
With Extended Clinical Follow Up

John R. Goldblum, M.D.; John D. Reith, M.D.; Sharon W. Weiss, M.D.

From the Departments of Anatomic Pathology of the Cleveland Clinic
Foundation, Cleveland, Ohio, U.S.A. (J.R.G.); University of Florida,
Gainesville, Florida

Am J Surg Pathol 2000;24:1125-1130 Abstract quote

There is a prevailing view that sarcomas arising in dermatofibrosarcoma
protuberans (DFSP) have a higher risk of metastasis than ordinary DFSP,
but these data are based on cases with variable and often suboptimal
treatment. There has not been a large study of sarcomas arising in DFSP
in which all cases were treated by wide local excision, thereby arguably
altering outcome.

Clinicopathologic features of 18 cases of sarcomas arising in DFSP
treated by wide local excision and having follow up of at least 5 years
were analyzed.

An estimate of the proportion of sarcoma and DFSP was made. The number
of mitotic figures and degree of CD34 immunoreactivity were assessed
in each case. The cohort included 13 females and 5 males (age, 23–87
yrs; median, 47 yrs). The tumors involved the trunk (7), scalp (4),
extremities (4), and inguinal region (3), and ranged from 1.5 to 7 cm
(median, 4 cm). Sarcoma occurred de novo in 15 cases and in a recurrence
in three. Sarcomas resembled fibrosarcoma (17) or malignant fibrous
histiocytoma (1) and occupied between 20% and 80% of the tumor (median,
60%). Mitotic activity ranged from 2 to 16 per 10 high-power field (HPF;
median 7 per 10 HPF) in the sarcomatous component and 0 to 3 per 10
HPF (median, 1 per 10 HPF) in the DFSP component. All tumors expressed
CD34 in the DFSP component but only nine (50%) in the sarcomatous component.
All patients were treated by wide local excision with negative margins;
three additionally received radiation. Four patients (22%) developed
recurrences, but none developed metastasis during the follow-up period
of 62 months to 17 years (median, 81.5 mos).

In contrast to earlier studies, we demonstrate that patients with
sarcomas arising in DFSP do not have an increased risk of distant metastasis
within a 5-year follow-up period, provided they are treated by wide
local excision with negative margins. This probably reflects the fact
that wide local excision results in eradication of local tumor, thereby
eliminating the source for subsequent dissemination. However, we cannot
completely exclude the possibility that tumors in which clear margins
are achieved represent a less aggressive subset, as has been suggested
for high-grade extremity sarcomas.